A research team has demonstrated that a cell-penetrating molecule called TAT transported human frataxin protein to its proper place in cells, where it normalized growth, improved heart structure and function, and increased survival rate and life span in a mouse model of severe Friedreich’s ataxia (FA).
The team also showed that the TAT delivery method worked in cultured FA-affected human cells called fibroblasts (which mature into any of a variety of connective tissue types). In these experiments, targeted delivery of frataxin protein to cellular “energy factories” called mitochondria caused a reduction in toxicity that results from a cell-damaging phenomenon called oxidative stress.
The TAT molecule (for transactivator of transcription) is able to pass through cellular membranes, thereby gaining entry to cells. Once inside, the molecule also is able to pass through intracellular (within the cell) membranes such as those encapsulating the mitochondria. This cell-penetrating ability allows TAT molecules to deliver molecular “cargo” such as small molecules, DNA fragments or, in this case, frataxin protein.
The product of linking, or fusing, TAT with frataxin is the TAT-Frataxin “fusion” protein, or TAT-FXN.
The research team was led by R. Mark Payne at the Riley Heart Research Center, Indiana University School of Medicine in Indianapolis, with colleagues at that institution and also at Wake Forest University School of Medicine in Winston-Salem, N.C.
The team reported its findings online Dec. 8, 2011, in Human Molecular Genetics. (See A TAT-Frataxin fusion protein increases life span and cardiac function in a conditional Friedreich’s ataxia mouse model.)
FA is a neurological disorder that causes loss of balance and coordination (ataxia), difficulty with speech and swallowing, muscle weakness, skeletal abnormalities and cardiac (heart) abnormalities. The underlying cause of FA is a deficiency of the frataxin protein, resulting in diminished energy production in cells — including those of the nervous system and heart.
It’s thought that increasing frataxin levels or finding ways to replicate the functions normally performed by the missing protein potentially may be therapeutic strategies in FA.
The researchers noted that data support the continued study of TAT-FXN as a protein replacement therapy in FA.
See also FA: A Case of Impaired Ironworks, Quest magazine, January-March 2011.